The euactinomycetes are a subset of a large and complex group of Gram-positive bacteria known as actinomycetes. Over the past few decades these organisms, which are abundant in soil, have generated significant commercial and scientific interest as a result of the large number of therapeutically useful compounds, particularly antibiotics, produced as secondary metabolites. The intensive search for strains able to produce new antibiotics has led to the identification of hundreds of new species.
Many of the euactinomycetes, particularly Streptomyces and the closely related Saccharopolyspora genera, have been extensively studied. Both of these genera produce a notable diversity of biologically active metabolites. Because of the commercial significance of these compounds, much is known about the genetics and physiology of these organisms. A number of cyclic hexadepsipeptides have been isolated from Streptomyces species. For example, aurantimycins (Gräfe, U. et al. (1995), J. of Antibiotics, Vol. 48, no. 2, 119-125); azinothricin (Maehr, H. et al. (1986), J. of Antibiotics, Vol 39, no 1, 17-25); GE3 and GE3B (Sakai, Y. et al. (1997), J. of Antibiotics, vol 50, no 8, 659-664); and polyoxypeptins A and B (Umezawa K. et al. (1998), Tet. Lett., Vol 39, 1389-92; Umezawa K. et al. (1999), J. Org. Chem., Vol 64, no 9, 3034-8; and Umezawa K. et al. (1998), Adv. Enzyme Regul., vol 39, 145-156; and WO 98/56809, Takeuchi et al.).
Although many biologically active compounds have been identified from bacteria, there remains the need to obtain novel compounds with enhanced properties. Thus, there exists a considerable need to obtain pharmaceutically active compounds in a cost-effective manner and with high yield. The present invention solves these problems by providing new therapeutic compounds and methods to generate these novel compounds by fermentation and optional post-biosynthetic chemical modifications.